Autoimmune hemolytic anemias and igg antierythrocyte autoantibodies in waldenström's macroglobulinemia: association with fcγriia polymorphism

Access through your institution Buy or subscribe Autoimmune hemolytic anemia (AIHA) and cryoglobulinemia, occur at diagnosis or later both in 10–20% of patients with Waldenström's

Macroglobulinemia (WM).1, 2 Immunoglobulin G fragment C (Fc_γ_)-mediated erythrophagocytosis has been recognized as the major pathogenic mechanism responsible for AIHA.3, 4 The clearance of

immune complexes and the efficacy of their phagocytosis by splenic macrophages depend on the interactions between Fc_γ_ receptors (Fc_γ_R) and immunoglobulin G (IgG).3 Therefore, genetic

polymorphisms that modulate the affinity of Fc_γ_RIIa and Fc_γ_RIIIa for IgG may influence these processes. The phenotypic expression of valine (V) or phenylalanine (F) at amino acid 158 of

Fc_γ_RIIIa receptor (Fc_γ_RIIIa-158V/F polymorphism) is associated with higher or lower affinity for IgG1 and IgG3.3 Consequently, the homozygous Fc_γ_RIIIa-158F genotype is associated with

a lower response rate to rituximab therapy.2 Similarly, Fc_γ_RIIa gene displays a G to A point mutation in the ligand binding domain, causing an arginine (R) to histidine (H) amino-acid

substitution at position 131.3 Both alleles bind IgG1 and IgG3. The Fc_γ_RIIa-131H allele has a higher affinity for IgG2 than Fc_γ_RIIa-131R allele,3 whereas Fc_γ_RIIa-131R is more efficient

than Fc_γ_RIIa-131H for mediating C-reactive protein (CRP)-dependent phagocytosis.5 C-reactive protein is an acute phase serum protein involved in the recognition of products of damaged

autologous cells, and elevated serum concentrations have been described in lymphoproliferative disorders, especially WM. In addition, the Fc_γ_RIIa is involved in immune complex and

cryoglobulin-induced production of cytokines, such as interleukin (IL)-6 and IL-10, two cytokines of importance for B-cell malignant disorders.6 The Fc_γ_RIIa-R/H131 polymorphism influences

the development of several autoimmune disorders such as systemic lupus erythematosus.3 Therefore, we evaluated the relationships between the Fc_γ_RIIa-131R/H and Fc_γ_RIIIa-158V/F

polymorphisms, and clinical characteristics including AIHA and cryoglobulinemia in 74 WM patients. Seventy-four patients, with WM diagnosed and treated according to the recommendations

established during the second International Workshop on WM,2 were included in the study. Median age was 64 years (range 39–98 years, M/F=2) and informed consent was obtained from all

patients according to local institutions guidelines. Autoimmune hemolytic anemia was defined by the combination of an anemia (hemoglobin <12 g/dl), one or more laboratory signs of

hemolysis (reticulocytosis, decreased haptoglobin, increased bilirubin, or lactic dehydrogenase) and the presence of antierythrocyte autoantibody detected by the direct antiglobulin test

(DAT). Treatment initiation criteria2 and all AIHA diagnostic criteria, including positive DAT were assessed every 6 months. Twenty-two patients (29%) with asymptomatic WM remained untreated

at the date of the analysis. First-line therapy included chlorambucil (39 patients), combination chemotherapy (2), fludarabine alone (6) or in combination with other chemotherapy (3), and

rituximab alone (2). Rituximab and fludarabine were delivered later in 10 and 14 additional patients, respectively. There was no difference in the number of treatments, the use of

fludarabine and rituximab between the genotypic groups. Genomic DNA was extracted from peripheral blood using standard phenol–chloroform method. Genotyping for Fc_γ_RIIa-131R/H and

Fc_γ_RIIIa-158V/F polymorphisms were performed with a PCR-based restriction fragment length polymorphism assay. The clinical and laboratory characteristics in the different genotypic groups

were compared using the Yates modified _χ_2-test or the Fisher exact test. Cumulative incidences of competing risks were computed as previously described, estimates in each group of patients

were compared with the test proposed by Gray. Survival after first treatment initiation and overall survival were calculated from the date of the first-line therapy initiation and the date

of diagnosis, respectively, to the date of death or last follow-up evaluation, in the 59 patients diagnosed before 1 December 2003. The stopping date was 31 January 2005 and median follow-up

of alive patients was 55 months (14–253). Survival curves were compared using the log-rank test with bootstrap resampling (1000 replicates). All analyses were carried out using Splus 6.2

(MathSoft, Cambridge, MA, USA) software and the R1.8.1 language, especially the cmprsk package (2.1–3 version) developed by Gray (Cambridge, MA, USA). This is a preview of subscription

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ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support REFERENCES * Jonsson V, Kierkegaard A, Salling S, Molander S, Andersen LP,

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de la Somme de la Ligue contre le Cancer. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Service d’Hématologie -Immunologie-Cytogénétique, Centre Hospitalier, Valenciennes, France S Poulain 

& P Duthilleul * Service d’Hématologie Clinique, Centre Hospitalier Schaffner, Lens, France I Dervite, L Stalnikiewicz & P Morel * Service des Maladies du Sang, Centre Hospitalier

Regional Universitaire, Lille, France X Leleu, A-S Moreau, V Coiteux & S de Botton * Service d’Hématologie Clinique, Centre Hospitalier, Valenciennes, France J Fernandes Authors * S

Poulain View author publications You can also search for this author inPubMed Google Scholar * I Dervite View author publications You can also search for this author inPubMed Google Scholar

* X Leleu View author publications You can also search for this author inPubMed Google Scholar * J Fernandes View author publications You can also search for this author inPubMed Google

Scholar * L Stalnikiewicz View author publications You can also search for this author inPubMed Google Scholar * A-S Moreau View author publications You can also search for this author

inPubMed Google Scholar * V Coiteux View author publications You can also search for this author inPubMed Google Scholar * S de Botton View author publications You can also search for this

author inPubMed Google Scholar * P Duthilleul View author publications You can also search for this author inPubMed Google Scholar * P Morel View author publications You can also search for

this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to P Morel. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Poulain, S., Dervite,

I., Leleu, X. _et al._ Autoimmune hemolytic anemias and IgG antierythrocyte autoantibodies in Waldenström's macroglobulinemia: association with Fc_γ_RIIa polymorphism. _Leukemia_ 20,

1179–1181 (2006). https://doi.org/10.1038/sj.leu.2404199 Download citation * Published: 06 April 2006 * Issue Date: 01 June 2006 * DOI: https://doi.org/10.1038/sj.leu.2404199 SHARE THIS

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